This Program Project unites the efforts of 5 independent laboratories in studies of novel mechanisms of neural signal transduction and the modulation of synaptic efficacy. Despite substantial progress in describing the circuitry and cellular properties of the mammalian brain, the molecular events that control changes in synaptic strength within these circuits are only now beginning to be understood. This Program, organized into 3 Units, will use biochemical, molecular biological and electrophysiological methods to elucidate basic mechanisms of neural function and plasticity. Most Units will combine biochemical with physiologic studies and will be assisted in this by the Biochemistry Core. Since 1985, the joint efforts of Columbia University neuroscientists and biochemists experienced in eicosanoid biosynthesis have led to the recognition that arachidonic acid and its metabolites function as modulators in both vertebrate and invertebrate neurons. Future experiments will address the synthesis and function of eicosanoids and related second messenger systems in modulation of Ca2+ channels in sympathetic neurons (Siegelbaum & Role) and in activity-dependent plasticity in Aplysia neurons (Feinmark & Schwartz). The hippocampal LTD4 receptor (as a model for a family of leukotriene receptors will be cloned (Axel) and detailed biochemical and physiologic studies of 12-lipoxygenase-derived neuromodulators will continue (Feinmark & Schwartz). Results from the simple invertebrate nervous system will continue to suggest appropriate research directions in the mammalian brain. For example, they suggest that arachidonate metabolites are good candidates as retrograde messengers in long-term potentiation. On the other hand, physiological results from the vertebrate neural systems will help direct the biochemical analyses of these pathways in Aplysia. New insights into learning, neural development and regeneration are likely to emerge from the coordinated research proposed in this Program.